The present invention relates to a novel method for preparing a novel ipid-based cochleate delivery system, the preparations derived from the lipid-based cochleate delivery system, such as drugs, carbohydrates, vitamins, minerals, polynucleotides, polypeptides, lipids and the like, and the use of these preparations.
The ability of biologically relevant molecules to be administered via the oral route depends on several factors. The biologically relevant molecule must be soluble in the gastrointestinal fluids in order for the biologically relevant molecule to be transported across biological membranes for an active transport mechanism, or have suitable small particle size that can be absorbed through the Peyer""s Patches in the small intestine and through the lymphatic system. Particle size is an important parameter when oral delivery is to be achieved (see Couvreur et al, Adv. Drug Delivery Rev., 10:141-162 (1993)).
The primary issue in the ability to deliver drugs orally is the protection of the drug from proteolytic enzymes. An ideal approach is to incorporate the drug in a hydrophobic material so that the aqueous fluids cannot penetrate the system. Lipid-based cochleates are an ideal system that can achieve this purpose.
The advantages of cochleates are numerous. The cochleates have a nonaqueous structure and therefore they:
a) are more stable because of less oxidation of lipids;
b) can be stored lyophilized, which provides the potential to be stored for long periods of time at room temperatures, making them advantageous for worldwide shipping and storage prior to administration;
c) maintain their structure even after lyophilization, whereas liposome structures are destroyed by lyophilization;
d) exhibit efficient incorporation of biologically relevant molecules into the lipid bilayer of the cochleate structure;
e) have the potential for slow release of a biologically relevant molecule in vivo as cochleates dissociate;
f) have a lipid bilayer which serves as a carrier and is composed of simple lipids which are found in animal and plant cell membranes, so that the lipids are non-toxic;
g) are produced easily and safely;
h) can be produced as defined formulations composed of predetermined amounts and ratios of drugs or antigens.
Cochleate structures have been prepared first by D. Papahadjopoulos as an intermediate in the preparation of large unilamellar vesicles (see U.S. Pat. No. 4,078,052). The use of cochleates to deliver protein or peptide molecules for vaccines has been disclosed in U.S. Pat. Nos. 5,840,707 and 5,643,574. The use of cochleates to orally deliver drugs, nutrients, and flavors have been described in U.S. Pat. No. 5,994,318.
However, the advantages of using small-sized cochleates have only recently been explored. The effective oral delivery of drugs that are mediated by hydrogel-isolated cochleates has been described in U.S. application Ser. No. 09/235,400. However, the effective delivery of hydrogel-isolated cochleates have not been described for other biologically relevant molecules such as drugs, polypeptides, polynucleotides, antigens, vitamins, minerals, amino acids, saccharides, flavor oils, and the like.
Accordingly, it is an object of this invention to provide a method for obtaining a hydrogel-isolated cochleate of a particle size of less than one micron. The method further comprises the steps required to encochleate at least one biologically relevant molecule in the hydrogel-isolated cochleates in an effective amount.
A xe2x80x9cbiologically relevant moleculexe2x80x9d is one that has a role in the life processes of a living organism. The molecule may be organic or inorganic, a monomer or a polymer, endogenous to a host organism or not, naturally occurring or synthesized in vitro, and the like. Thus, examples include vitamins, minerals, flavors, amino acids, toxins, microbicides, microbistats, co-factors, enzymes, polypeptides, polypeptide aggregates, polynucleotides, lipids, carbohydrates, nucleotides, starches, pigments, fatty acids, hormones, cytokines, viruses, organelles, steroids and other multi-ring structures, saccharides, metals, metabolic poisons, drugs, and the like.
These and other objects have been obtained by providing an encochleated biologically relevant molecule, wherein the biologically relevant molecule-cochleate comprises the following components:
a) a biologically relevant molecule,
b) a negatively charged lipid, and
c) a cation component,
wherein the article size of the cochleate is less than one micron.